Immunological imprinting of the antibody response in COVID-19 patients

Aydillo, Teresa; Rombauts, Alexander; Stadlbauer, Daniel; Aslam, Sadaf; Abelenda-Alonso, Gabriela; Escalera, Alba; Amanat, Fatima; Jiang, Kaijun; Krammer, Florian; Carratalà, Jordi; Garcı́a-Sastre, Adolfo

doi:10.1038/s41467-021-23977-1

Cited by 162 publications

(166 citation statements)

References 52 publications

(43 reference statements)

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“…Aydillo et al have described that during SARS-CoV-2 infection in hospitalized COVID-19 patients, there is also an increase in antibodies to conserved, but not variable, regions of HCoV-OC43 and HCoV-HKU1 β coronaviruses spike protein, so-called back-boosting. 17 Such a back-boosting effect was also described by Song et al . 18 In our cohort, we have analyzed the antibody response to SARS-CoV-2 infection in severe COVID-19 patients, but did not find concomitant substantial increase in antibody titers against spike S1 proteins from circulating β coronaviruses, nor α coronaviruses for that matter.…”

Section: Back Boosting Of Existing Memorysupporting

confidence: 55%

The “original antigenic sin” and its relevance for SARS-CoV-2 (COVID-19) vaccination

Rijkers

Overveld

2021

Clinical Immunology Communications

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Imprinting of the specific molecular image of a given protein antigen into immunological memory is one of the hallmarks of immunity. A later contact with a related, but different antigen should not trigger the memory response (because the produced antibodies would not be effective). The preferential expansion of cross-reactive antibodies, or T-lymphocytes for that matter, by a related antigen has been termed the original antigenic sin and was first described by Thomas Francis Jr. in 1960. The phenomenon was initially described for influenza virus, but also has been found for dengue and rotavirus. The antibody dependent enhancement observed in feline coronavirus vaccination also may be related to the original antigenic sin. For a full interpretation of the effectivity of the immune response against SARS-CoV-2, as well as for the success of vaccination, the role of existing immunological memory against circulating corona viruses is reviewed and analyzed.

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Section: Back Boosting Of Existing Memorysupporting

confidence: 55%

The “original antigenic sin” and its relevance for SARS-CoV-2 (COVID-19) vaccination

Rijkers

Overveld

2021

Clinical Immunology Communications

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“…They account for about 10% of all acute respiratory tract infections, and thus, a substantial proportion of the global population is expected to carry antibodies against them 27,28 , although their protective immunity might be short-lasting 29 . Previous studies found some cell-mediated 30,31 and antibody cross-reactivity of HCoV immune responses with SARS-CoV-2 [32][33][34] . Regions within N and S antigens with high amino acid homology between SARS-CoV-2 and HCoV are potential targets of cross-reactive antibodies [33][34][35][36] , and could exert cross-protective effects against SARS-CoV-2 infection and/or disease.…”

mentioning

confidence: 95%

“…Some recent studies have suggested that this pre-existing immunity would not confer cross-protection but, rather, be responsible for an immunological imprinting or 'original antigenic sin', a phenomenon well studied for influenza virus infections. This suggests that the immune system privileges recall of existing memory responses -in this case of HCoV-, in detriment of stimulating de novo responses -here to SARS-CoV-2-leading to poor outcomes or severe disease 31,32 . The possibility of antibodies to HCoVs acting as antibody-derived enhancement (ADE) has also been reviewed and the most recent evidence shows no clinical, in vitro or animal evidence 40,41 .…”

mentioning

confidence: 99%

Seven-month kinetics of SARS-CoV-2 antibodies and role of pre-existing antibodies to human coronaviruses

et al. 2021

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Unraveling the long-term kinetics of antibodies to SARS-CoV-2 and the individual characteristics influencing it, including the impact of pre-existing antibodies to human coronaviruses causing common cold (HCoVs), is essential to understand protective immunity to COVID-19 and devise effective surveillance strategies. IgM, IgA and IgG levels against six SARS-CoV-2 antigens and the nucleocapsid antigen of the four HCoV (229E, NL63, OC43 and HKU1) were quantified by Luminex, and antibody neutralization capacity was assessed by flow cytometry, in a cohort of health care workers followed up to 7 months (N = 578). Seroprevalence increases over time from 13.5% (month 0) and 15.6% (month 1) to 16.4% (month 6). Levels of antibodies, including those with neutralizing capacity, are stable over time, except IgG to nucleocapsid antigen and IgM levels that wane. After the peak response, anti-spike antibody levels increase from ~150 days post-symptom onset in all individuals (73% for IgG), in the absence of any evidence of re-exposure. IgG and IgA to HCoV are significantly higher in asymptomatic than symptomatic seropositive individuals. Thus, pre-existing cross-reactive HCoVs antibodies could have a protective effect against SARS-CoV-2 infection and COVID-19 disease.

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“…Numerous studies have observed elevated responses to endemic CoV following SARS-CoV-2 infection [23][24][25][26][27] , and more recent work has shown that the magnitude of this "back-boosting" effect is inversely correlated with the induction of IgG and IgM against to SARS-CoV-2 spike (S) protein 28 . Given differential degrees of homology between the receptor binding domain (RBD) in S1 that is the target of the majority of neutralizing antibodies, and the better conserved S2 domain that may be the target of antibodies with diverse effector functions but which are rarely neutralizing, the original antigenic sin hypothesis suggests that lower titers of neutralizing antibodies against SARS-CoV-2 may result from boosting of pre-existing cross-reactive lineages.…”

Section: Introductionmentioning

confidence: 99%

Boosting of Cross-Reactive Antibodies to Endemic Coronaviruses by SARS-CoV-2 Infection but not Vaccination with Stabilized Spike

Crowley

Natarajan

Hederman

et al. 2021

Preprint

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Pre-existing antibodies to endemic coronaviruses (CoV) that cross-react with SARS-CoV-2 have the potential to influence the antibody response to COVID-19 vaccination and infection for better or worse. In this observational study of mucosal and systemic humoral immunity in acutely infected, convalescent, and vaccinated subjects, we tested for cross reactivity against endemic CoV spike (S) protein at subdomain resolution. Elevated responses, particularly to the β-CoV OC43, were observed in all natural infection cohorts tested and were correlated with the response to SARS-CoV-2. The kinetics of this response and isotypes involved suggest that infection boosts preexisting antibody lineages raised against prior endemic CoV exposure that cross react. While further research is needed to discern whether this recalled response is desirable or detrimental, the boosted antibodies principally targeted the better conserved S2 subdomain of the viral spike and were not associated with neutralization activity. In contrast, vaccination with a stabilized spike mRNA vaccine did not robustly boost cross-reactive antibodies, suggesting differing antigenicity and immunogenicity. In sum, this study provides evidence that antibodies targeting endemic CoV are robustly boosted in response to SARS-CoV-2 infection but not to vaccination with stabilized S, and that depending on conformation or other factors, the S2 subdomain of the spike protein triggers a rapidly recalled, IgG-dominated response that lacks neutralization activity.Graphical AbstractGraphical AbstractAntibody responses to SARS-CoV-2 and endemic CoV spike proteins were measured in diverse cohorts. While antibodies to SARS-CoV-2 were induced across all isotypes, only IgA and IgG responses to endemic CoV were robustly boosted, and only among naturally-infected but not vaccinated individuals. These recalled, cross-reactive responses to endemic CoV primarily recognized the better conserved S2 domain and were non-neutralizing. While other antiviral activities of broadly cross-reactive S2-specifc antibodies are not known, the differing antigenicity of natural infection and vaccination with stabilized pre-fusion spike has potential implications for the breadth and level of protection afforded by each.

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Immunological imprinting of the antibody response in COVID-19 patients

Cited by 162 publications

References 52 publications

The “original antigenic sin” and its relevance for SARS-CoV-2 (COVID-19) vaccination

The “original antigenic sin” and its relevance for SARS-CoV-2 (COVID-19) vaccination

Seven-month kinetics of SARS-CoV-2 antibodies and role of pre-existing antibodies to human coronaviruses

Boosting of Cross-Reactive Antibodies to Endemic Coronaviruses by SARS-CoV-2 Infection but not Vaccination with Stabilized Spike

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